The last decade of research in intellectual and developmental disabilities (IDD) has been notably characterized by rapid advances in understanding the nature and complexity of inherited susceptibilities to IDD, but genetic discovery has not yet fulfilled the promise of more effective intervention, even for monogenic IDD syndromes. It is the immediate priority of a next generation of research to capitalize upon knowledge about causation in IDD (both genetic and environmental) and translate it into higher-impact intervention for as many individuals and families affected as possible. In the second cycle of the IDDRC at Washington University in St. Louis (IDDRC@WUSTL), our strategy for contributing to this effort preserves our Center's original focus on characterization of white matter injury to the newborn brain, but extends the scope of Core activity to facilitate a comprehensive approach to understanding and preventing developmental disorders of neural connectivity at the respective levels of cell, synapse, circuit, and behavior, and brings on line major strengths of WUSTL in genomics, behavioral/cognitive neuroscience, and clinical-translational science. The overarching goals of our Center are as follows: (1) To facilitate high-caliber, translational research on the pathogenesis and treatment of IDDs by sustaining an innovative Core structure that attracts and supports qualified, collaborative investigators, and interacts synergistically with complementary Core facilities of other U.S. IDDRCs. We propose to support an Administrative Core, a Developmental Neuroimaging Core, a Model Systems Core (encompassing capacity and expertise for both animal and cellular models of IDD), and a Clinical Translational Core. (2) To cultivate nodes of interdisciplinary scientific activity in frotiers of IDD research which are critical for the derivation of higher-impact treatment and preventive intervention, across 4 major themes: (i) The prevention of prematurity and its neurodevelopmental consequences; (ii) The elucidation of robust intermediate DD phenotypes (as markers of pathogenic processes, targets of early intervention, and indices of response to treatment); (iii) In-depth characterization of the developing human brain, and (iv) Functional genomic approaches to elucidating convergent mechanisms of IDD pathogenesis. (3) To conduct a signature research project that represents a bold, critical step toward higher-impact intervention for IDD, capitalizes upon both the Core structure of our IDDRC and institutional strengths at WUSTL, and epitomizes the manner in which our IDDRC facilitates trans-disciplinary research. Our project is designed to elucidate mechanisms of sex-specific modulation-of-expression of inherited risk for autism spectrum disorders, at the respective levels of cell, brain, and behavior. A goal is to identify compensatory mechanisms underlying resilience among females in ASD-affected families, for the purpose of recapitulating those mechanisms in novel interventions which would be of major relevance to a large proportion of the population of individuals at risk or affected by familial autistic syndromes.